1. Field of the Invention
This invention pertains to substituted heterocyclic derivatives which inhibit platelet aggregation.
2. Related Art
Fibrinogen is a glycoprotein present as a normal component of blood plasma. It participates in platelet aggregation and fibrin formation in the blood clotting mechanism.
Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an injury, the platelets binding to fibrinogen will initiate aggregation and form a thrombus. Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as gpIIb/IIIa; this is an important feature of the platelet function. Inhibitors of this interaction are useful in modulating or preventing platelet thrombus formation.
It is also known that another large glycoprotein named fibronectin, which is a major extracellular matrix protein, interacts with fibrinogen and fibrin, and with other structural molecules such as actin, collagen and proteoglycans. Various relatively large polypeptide fragments in the cell-binding domain of fibronectin have been found to have cell-attachment activity. (See U.S. Pat. Nos. 4,517,686, 4,589,881, and 4,661,111). Certain relatively short peptide fragments from the same molecule were found to promote cell attachment to a substrate when immobilized on the substrate or to inhibit attachment when in a solubilized or suspended form. (See U.S. Pat. Nos. 4,578,079 and 4,614,517).
In U.S. Pat. No. 4,683,291, inhibition of platelet function is disclosed with synthetic peptides designed to be high affinity antagonists of fibrinogen binding to platelets. U.S. Pat. No. 4,857,508 discloses tetrapeptides having utility as inhibitors of platelet aggregation.
Other synthetic peptides and their use as inhibitors of fibrinogen binding to platelets are disclosed by Koczewiak et al., Biochem. 23, 1767-1774 (1984); Plow et al., Proc. Natl. Acad. Sci. 82, 8057-8061 (1985); Ruggeri et al., Ibid. 83, 5708-5712 (1986); Ginsberg et al., J. Biol. Chem. 260 (7), 3931-3936 (1985); Haverstick et al., Blood 66 (4), 946-952 (1985); and Ruoslahti and Pierschbacher, Science 238, 491-497 (1987). Still other such inhibitory peptides are disclosed in EP Pat. Applications 275,748 and 298,820.
U.S. Pat. No. 4,879,313 discloses compounds useful as inhibitors of platelet aggregation having the formula: ##STR1## wherein x=6 to 10,
y=0 to 4, PA1 Z=H, COOH, CONH2 or C1-6 alkyl, PA1 Ar=phenyl, biphenyl or naphthyl, each substituted with 1 to 3 methoxy groups, or an unsubstituted phenyl, biphenyl, naphthyl, pyridinyl or thienyl group, and PA1 Asp=aspartic acid residue. PA1 R.sup.2 is selected from monocyclic, bicyclic or tricyclic heterocyclyl radicals in which 1 to about 3 heteroatoms are independently selected from oxygen, nitrogen and sulfur, which are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, carboxyl, sulfonyl, trifluoromethyl, amino, acyloxy, phenyl and naphthyl which are optionally substituted with halogen, nitro, lower alkoxy, and lower alkyl; PA1 A is selected from the group consisting of lower alkyl radicals, lower alkenyl radicals, lower alkynyl radicals, alicyclic radicals, wherein all of said radicals are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, aromatic hydrocarbons which are optionally substituted with halogen, nitro, lower alkoxy and lower alkyl; PA1 W is selected from the group consisting of hydrogen, lower alkyl radicals, lower alkenyl radicals, lower alkynyl radicals, alicyclic hydrocarbon radicals and aromatic hydrocarbon radicals, wherein all of said radicals are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, amino, acyloxy, phenyl and naphthyl which may be optionally substituted with halogen, nitro, lower alkoxy, and lower alkyl; PA1 Z, Z', Z" are independently selected from the group consisting of hydrogen, lower alkyl radicals, halogen, alkoxy, cyano, sulfonyl, carboxyl, and hydroxyl radicals; and PA1 q is an integer from 0 to about 6. PA1 R.sup.1 is preferably selected from the group consisting of hydrogen,lower alkyl, aromatic hydrocarbon radicals; more preferably hydrogen, lower alkyl, benzyl, and phenyl; even more preferably hydrogen, lower alkyl and benzyl radicals; most preferably hydrogen. PA1 R.sup.1 is preferably optionally substituted with nitro, amino or lower alkoxy. PA1 R.sup.2 is preferably pyridinyl, pyrimidinyl, furanyl, thiophenyl or benzodioxolyl radicals which are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, carboxyl, sulfonyl, trifluoromethyl and amino; more preferably pyridinyl and pyrimidinyl and benzodioxolyl; even more preferably pyridinyl. PA1 R.sup.2 is preferably optionally substituted with nitro, amino or lower alkoxy. PA1 A is preferably lower alkyl,lower alkenyl radicals and lower alicyclic hydrocarbon radicals; more preferably lower alkyl or cyclopropylene. PA1 W is preferably selected from pivaloyloxymethyl acyloxymethyl, hydrogen and lower alkyl radicals and more preferably is hydrogen and lower alkyl. PA1 Z, Z', Z" are preferably hydrogen. PA1 q is preferably 0 to about 4; more preferably 0 to about 2; most preferred 0. PA1 wherein R.sup.1 is selected from hydrogen, lower alkyl radicals of 1 to about 6 carbon atoms, lower alkenyl radicals of 2 to about 6 carbon atoms, lower alkynyl radicals of 2 to about 8 carbon atoms, alicyclic hydrocarbon radicals of 3 to about 6 carbon atoms, aromatic hydrocarbon radicals, wherein all of said radicals are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, carboxyl, sulfonyl, and trifluoromethyl; PA1 R.sup.2 is selected from monocyclic or bicyclic heterocyclyl radicals in which 1 to about 3 heteroatoms are independently selected from oxygen, nitrogen and sulfur which are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, carboxyl, sulfonyl, trifluoromethyl and amino; PA1 A is selected from lower alkyl radicals of 1 to about 6 carbon atoms, lower alkenyl radicals of 2 to about 6 carbon atoms, lower alkynyl radicals of 2 to about 4 carbon atoms, and alicyclic hydrocarbon radicals of 3 to about 5 carbon atoms, wherein said radicals are optionally substituted with hydroxyl, lower alkoxy, and halogen; PA1 W is selected from hydrogen, lower alkyl radicals of 1 to about 6 carbon atoms, lower alkenyl radicals of 2 to about 6 carbon atoms, alicyclic hydrocarbon radicals of 3 to about 6 carbon atoms, and aromatic hydrocarbon radicals of 6 to about 12 carbon atoms, wherein all of said radicals are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, amino, and acyloxy; PA1 Z, Z', Z" are independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, sulfonyl, carboxyl and lower alkyl radicals. PA1 q is an integer from 0 to about 6. PA1 R.sup.1 is preferably hydrogen. PA1 R.sup.2 is preferably pyridinyl and pyrimidinyl and more preferably pyridinyl. PA1 A is preferably lower alkyl of 1 to about 6 carbon atoms. PA1 W is preferably selected from pivaloyloxymethyl acyloxymethyl, hydrogen and lower alkyl radicals and more preferably is hydrogen and lower alkyl; most preferably hydrogen and ethyl. PA1 Z, Z', Z" are preferably hydrogen. PA1 wherein R.sup.1 is selected from hydrogen, lower alkyl radicals, phenyl radicals, benzyl radicals, substituted phenyl radicals wherein each substituent are selected from the group consisting of halogen, lower alkyl, lower alkoxy and carboxyl radicals; PA1 R.sup.2 is selected from monocyclic or bicyclic heterocyclyl radicals in which 1 to about 3 heteroatoms are nitrogen which are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, carboxyl, sulfonyl, trifluoromethyl and amino; PA1 A is selected from lower alkyl radicals and lower alkenyl radicals and lower alicyclic hydrocarbon radicals; PA1 W is selected from the group consisting of hydrogen and lower alkyl radicals; PA1 Z, Z', Z" are independently selected from the group consisting of halogen and hydrogen, and alkoxy, and lower alkyl radicals; and PA1 q is an integer from 0 to about 6. PA1 R.sup.1 is preferably hydrogen, lower alkyl radicals, phenyl radicals; more preferably hydrogen. PA1 R.sup.2 is preferably pyridinyl and pyrimidinyl; more preferably pyridinyl, PA1 A is preferably lower alkyl. PA1 W is preferably selected from hydrogen and lower alkyl radicals; more preferably hydrogen and ethyl. PA1 Z, Z', Z" are preferably hydrogen. PA1 q is preferably an integer 0 to about 4; more preferably 0 to about 2 and most preferably 0.
European Patent Application 372,486 discloses N-acyl beta amino acid derivatives of the formula: ##STR2## and their salts. Said compounds are useful for inhibiting platelet aggregation in the treatment of thrombosis, stroke, myocardial infarction, inflammation and arteriosclerosis, and for inhibiting metastasis.
European Patent Application 381,033 discloses amidino or guanidinoaryl substituted alkanoic acid derivatives useful for the treatment of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis and tumors.
European Patent Application 445,796 discloses Acetic Acid derivatives useful as a ligand for adhesive proteins on platelets. As such these compounds are useful to modulate and/or inhibit platelet aggregation.